Carisprodol Articles and Methods

ABSTRACT

A method of using carisoprodol comprises informing a user that administration of carisoprodol in the presence of food decreases the C max  for carisoprodol compared to administration in the absence of food. In one embodiment, informing comprises providing printed labeling instructions. Also included are articles comprising a carisoprodol formulation and prescribing information, and methods of manufacturing carisoprodol dosage forms. Included are measures intended to increase the safe use of narrow therapeutic medications with carisoprodol.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.11/425,175, filed Jun. 20, 2006, which claims priority from U.S.Provisional Application Ser. No. 60/790,202 filed Apr. 7, 2006, each ofwhich is hereby incorporated by reference in its entirety.

BACKGROUND

Carisoprodol, chemical nameN-isopropyl-2-methyl-2-propyl-1,3-propanediol dicarbamate, is apharmaceutical active agent whose metabolite is meprobamate. Metabolismof carisoprodol by cytochrome p450 isoform CYP2C19 has been reported.Carisoprodol was approved by the U.S. FDA on Apr. 9, 1959. It ismarketed in the United States under the brand name Soma®, and in theUnited Kingdom and other countries under the brand name Carisoma®.Carisoprodol is commonly used as a skeletal muscle relaxant.

Carisoprodol is a colorless, crystalline powder, having a mild,characteristic odor and a bitter taste. It is very sparingly soluble inwater and freely soluble in alcohol, chloroform, and acetone.

Further in relation to sparingly water soluble drugs, it has beenreported that some such drugs are formulated into dosage forms thatexhibit improved absorption into the blood stream when administered withfood. The plasma concentrations of griseofulvin, for example, aregreatly improved when taken in the presence of fatty foods.Pharmacokinetic studies have not been reported to date to evaluate theeffect of food on the pharmacokinetics of carisoprodol.

In addition, studies directed to possible negative or competinginteractions with other active agents have been limited. While theCarisoma® label lists several drugs whose blood levels may be affectedby coadministration with carisoprodol, little information is availablethat quantifies these effects.

The present invention addresses the need for improved carisoprodolarticles and methods of administering carisoprodol.

SUMMARY

There is an especially important need for improvements in carisoprodolarticles and methods because the experimentally observed effect of foodon the blood levels of this poorly water soluble drug was the oppositeof what would normally be expected.

A method of using carisoprodol comprises informing a user thatadministration of carisoprodol in the presence of food decreases theC_(max) of carisoprodol compared to administration in the absence offood.

A method of using carisoprodol comprises informing a user thatadministration of carisoprodol in the presence of food decreases theC_(max) of carisoprodol compared to administration in the absence offood, and that an AUC of carisoprodol is substantially unchanged in thepresence and absence of food.

A method of using carisoprodol comprises obtaining carisoprodol from acontainer providing information that administration of carisoprodol inthe presence of food decreases the C_(max) of carisoprodol compared toadministration in the absence of food.

A method of manufacturing a carisoprodol pharmaceutical compositioncomprises packaging a carisoprodol pharmaceutical formulation along withinformation that administration of carisoprodol in the presence of fooddecreases the C_(max) for carisoprodol compared to administration in theabsence of food.

An article of manufacture comprises a container holding a dosage form ofcarisoprodol, wherein the container is associated with printed labelinginstructions advising that administration of carisoprodol in thepresence of food decreases the C_(max) of carisoprodol compared toadministration in the absence of food.

A method of using carisoprodol comprises informing a user that thecarisoprodol should be administered under fasted conditions, on an emptystomach, without food, greater than about 1 hour prior to a meal, atleast about 2 hours after consumption of a meal, or a combination of oneor more of the foregoing statements.

An article of manufacture comprises a container holding a dosage formsuitable for administration of carisoprodol, and printed labelinginstructions informing that the carisoprodol should be administeredunder fasted conditions, on an empty stomach, without food, greater thanabout 1 hour prior to a meal, at least about 2 hours after consumptionof a meal, or a combination comprising one or more of the foregoingstatements.

A method of using carisoprodol comprises informing a user thatcarisoprodol affects activity of cytochrome p450 isozyme CYP2C19; andthat administration of carisoprodol with a substance with or withoutfood can affect the plasma concentration, bioavailability, safety,efficacy, or a combination comprising at least one of the foregoing ofcarisoprodol or the substance.

A method of using carisoprodol comprises informing a user thatcarisoprodol affects activity of cytochrome p450 isozyme CYP2C19; andthat administration of carisoprodol with a narrow therapeutic index drugwith or without food can affect the plasma concentration,bioavailability, safety, efficacy, or a combination comprising at leastone of the foregoing of carisoprodol or the narrow therapeutic indexdrug.

A method of using carisoprodol comprises informing a user that duringadministration of carisoprodol with a substance with or without food,the T_(max) for carisoprodol and the T_(max) for the substance should beconsidered when determining the timing of administration of thecarisoprodol and the substance.

A method of using carisoprodol comprises informing a user thatadministration of carisoprodol with an active agent that is a CYP2C19,substrate having a narrow therapeutic index can affect plasmaconcentration, bioavailability, safety, efficacy, or a combinationcomprising at least one of the foregoing of the active agent, whereinadministration is with or without food.

A method of using carisoprodol comprises obtaining carisoprodol from acontainer providing information that administration of carisoprodol withan active agent that is a CYP2C 19 substrate having a narrow therapeuticindex can affect plasma concentration, bioavailability, safety,efficacy, or a combination comprising at least one of the foregoing ofthe active agent, wherein administration is with or without food.

These and other embodiments, advantages and features of the presentinvention become clear when detailed description and examples areprovided in subsequent sections.

DETAILED DESCRIPTION

An “active agent” means a compound, element, or mixture that whenadministered to a patient, alone or in combination with anothercompound, element, or mixture, confers, directly or indirectly, aphysiological effect on the patient. The indirect physiological effectmay occur via a metabolite or other indirect mechanism. When the activeagent is a compound, then salts, solvates (including hydrates) of thefree compound or salt, crystalline forms, non-crystalline forms, and anypolymorphs of the compound are contemplated herein. Compounds maycontain one or more asymmetric elements such as stereogenic centers,stereogenic axes and the like, e.g., asymmetric carbon atoms, so thatthe compounds can exist in different stereoisomeric forms. Thesecompounds can be, for example, racemates or optically active forms. Forcompounds with two or more asymmetric elements, these compounds canadditionally be mixtures of diastereomers. For compounds havingasymmetric centers, all optical isomers in pure form and mixturesthereof are encompassed. In addition, compounds with carbon-carbondouble bonds may occur in Z- and E-forms, with all isomeric forms of thecompounds. In these situations, the single enantiomers, i.e., opticallyactive forms can be obtained by asymmetric synthesis, synthesis fromoptically pure precursors, or by resolution of the racemates. Resolutionof the racemates can also be accomplished, for example, by conventionalmethods such as crystallization in the presence of a resolving agent, orchromatography, using, for example a chiral HPLC column. All forms arecontemplated herein regardless of the methods used to obtain them.

“Pharmaceutically acceptable salts” includes derivatives ofcarisoprodol, wherein the carisoprodol is modified by making non-toxicacid or base addition salts thereof, and further refers topharmaceutically acceptable solvates, including hydrates, of suchcompounds and such salts. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid addition saltsof basic residues such as amines; alkali or organic addition salts ofacidic residues; and the like, and combinations comprising one or moreof the foregoing salts. The pharmaceutically acceptable salts includenon-toxic salts and the quaternary ammonium salts of the carisoprodol.For example, non-toxic acid salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; other acceptable inorganic salts include metalsalts such as sodium salt, potassium salt, cesium salt, and the like;and alkaline earth metal salts, such as calcium salt, magnesium salt,and the like, and combinations comprising one or more of the foregoingsalts. Pharmaceutically acceptable organic salts includes salts preparedfrom organic acids such as acetic, propionic, succinic, glycolic,stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic,hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic,esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like; organic amine saltssuch as triethylamine salt, pyridine salt, picoline salt, ethanolaminesalt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, and the like; and amino acid saltssuch as arginate, asparginate, glutamate, and the like; and combinationscomprising one or more of the foregoing salts.

“Efficacy” means the ability of an active agent administered to apatient to produce a therapeutic effect in the patient.

“Safety” means the incidence or severity of adverse events associatedwith administration of an active agent, including adverse effectsassociated with patient-related factors (e.g., age, gender, ethnicity,race, target illness, abnormalities of renal or hepatic function,co-morbid illnesses, genetic characteristics such as metabolic status,or environment) and active agent-related factors (e.g., dose, plasmalevel, duration of exposure, concomitant medication, or interactionswith concomitant medication).

Carisoprodol is a “very sparingly soluble” compound, having a solubilityin water of 0.3 to 1.4 mg/mL between 25 to 50° C.

A substance having a “narrow therapeutic index” (NTI) means a substancefalling within any definition of narrow therapeutic index as promulgatedby the U.S. Food and Drug Administration or any successor agencythereof, for example, a substance having a less than 2-fold differencein median lethal dose (LD50) and median effective dose (ED50) values forthe substance, or having a less than 2-fold difference in the minimumtoxic concentration and minimum effective concentration in the blood ofthe substance.

A “dosage form” means a unit of administration of an active agent.Examples of dosage forms include tablets, capsules, injections,suspensions, liquids, emulsions, creams, ointments, suppositories,inhalable forms, transdermal forms, and the like.

By “oral dosage form” is meant to include a unit dosage form for oraladministration. An oral dosage form may optionally comprise a pluralityof subunits such as, for example, microcapsules or microtablets.Multiple subunits may be packaged for administration in a single dose.

By “subunit” is meant to include a composition, mixture, particle,pellet, etc., that can provide an oral dosage form alone or whencombined with other subunits.

A dissolution profile is a plot of the cumulative amount of active agentreleased as a function of time. A dissolution profile can be measuredutilizing the Drug Release Test <724>, which incorporates standard testUSP 26 (Test <711>). A profile is characterized by the test conditionsselected such as, for example, apparatus type, shaft speed, temperature,volume, and pH of the dissolution medium. More than one dissolutionprofile may be measured. For example, a first dissolution profile can bemeasured at a pH level approximating that of the stomach, and a seconddissolution profile can be measured at a pH level approximating that ofone point in the intestine or several pH levels approximating multiplepoints in the intestine.

A highly acidic pH may be employed to simulate the stomach and a lessacidic to basic pH may be employed to simulate the intestine. By theterm “highly acidic pH” is meant a pH of about 1 to about 4. A pH ofabout 1.2, for example, can be used to simulate the pH of the stomach.By the term “less acidic to basic pH” is meant a pH of greater thanabout 4 to about 7.5, specifically about 6 to about 7.5. A pH of about 6to about 7.5, specifically about 6.8, can be used to simulate the pH ofthe intestine.

By “immediate-release” is meant a conventional or non-modified releasein which greater then or equal to about 75% of the active agent isreleased within two hours of administration, specifically within onehour of administration.

By “controlled-release” is meant a dosage form in which the release ofthe active agent is controlled or modified over a period of time.Controlled can mean, for example, sustained-, delayed- or pulsed-releaseat a particular time. Alternatively, controlled can mean that therelease of the active agent is extended for longer than it would be inan immediate-release dosage form, e.g., at least over several hours.

Dosage forms can be combination dosage forms having bothimmediate-release and controlled-release characteristics, for example, acombination of immediate-release pellets and controlled-release pellets.The immediate-release portion of a combination dosage form may bereferred to as a loading dose.

“Bioavailability” means the extent or rate at which an active agent isabsorbed into a living system or is made available at the site ofphysiological activity. For active agents that are intended to beabsorbed into the bloodstream, bioavailability data for a givenformulation may provide an estimate of the relative fraction of theadministered dose that is absorbed into the systemic circulation.“Bioavailability” can be characterized by one or more pharmacokineticparameters.

“Pharmacokinetic parameters” describe the in vivo characteristics of anactive agent (or surrogate marker for the active agent) over time, suchas plasma concentration (C), C_(max), C_(n), C₂₄, T_(max), and AUC.“C_(max)” is the measured concentration of the active agent in theplasma at the point of maximum concentration. “C_(n)” is the measuredconcentration of an active agent in the plasma at about n hours afteradministration. “C₂₄” is the measured concentration of an active agentin the plasma at about 24 hours after administration. The term “T_(max)”refers to the time at which the measured concentration of an activeagent in the plasma is the highest after administration of the activeagent. “AUC” is the area under the curve of a graph of the measuredconcentration of an active agent (typically plasma concentration) vs.time, measured from one time point to another time point. For exampleAUC_(0-t) is the area under the curve of plasma concentration versustime from time 0 to time t. The AUC_(0-∞) or AUC_(0-INF) is thecalculated area under the curve of plasma concentration versus time fromtime 0 to time infinity.

Bioequivalent means a product or method falling within a definition ofbioequivalent as promulgated by the U.S. Food and Drug Administration orany successor agency thereof. Under current U.S. FDA guidelines, twoproducts or methods (e.g., dosing under non-fasted versus fastedconditions) are bioequivalent if the 90% Confidence Intervals (CI) for alog transformed geometric mean of AUC_(0-INF), and C_(max) are 0.80 to1.25 (T_(max) measurements are not relevant to bioequivalence forregulatory purposes). To show bioequivalency between two compounds oradministration conditions pursuant to Europe's EMEA guidelines, the 90%CI for a log transformed geometric mean of AUC_(0-INF), must be 0.80 to1.25 and the 90% CI for a log transformed geometric mean of C_(max) mustbe 0.70 to 1.43.

Information as disclosed herein may include information that twoadministration methods are bioequivalent under FDA guidelines, aresubstantially bioequivalent, or have insignificant differences in theirpharmacokinetic parameters.

Certain formulations described herein may be “coated”. The coating maybe a suitable coating, such as, a functional or a non-functionalcoating, or multiple functional and/or non-functional coatings. By“functional coating” is meant to include a coating that modifies therelease properties of the total formulation, for example, asustained-release coating. By “non-functional coating” is meant toinclude a coating that is not a functional coating, for example, acosmetic coating. A non-functional coating can have some impact on therelease of the active agent due to the initial dissolution, hydration,perforation of the coating, etc., but would not be considered to be asignificant deviation from the non-coated composition.

“Informing” means referring to or providing, published material, forexample, providing an active agent with published material to a user; orpresenting information orally, for example, by presentation at aseminar, conference, or other educational presentation, by conversationbetween a pharmaceutical sales representative and a medical care worker,or by conversation between a medical care worker and a patient; ordemonstrating the intended information to a user for the purpose ofcomprehension.

A “medical care worker” means a worker in the health care field who mayneed or utilize information regarding an active agent including a dosageform thereof, including information on safety, efficacy, dosing,administration, or pharmacokinetics. Examples of medical workers includephysicians, pharmacists, physician's assistants, nurses, aides,caretakers (which can include family members or guardians), emergencymedical workers, and veterinarians.

A “patient” means a human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In some embodiments the patient is ahuman patient.

A “pharmaceutical supplier” means a person (other than a medical careworker), business, charitable organization, governmental organization,or other entity involved in the transfer of active agent, including adosage form thereof, between entities, for profit or not. Examples ofpharmaceutical suppliers include pharmaceutical distributors, pharmacychains, pharmacies (online or physical), hospitals, HMOs, supermarkets,the Veterans Administration, or foreign businesses or individualsimporting active agent into the United States.

A “user” means a patient, a medical care worker, or a pharmaceuticalsupplier.

A “product” or “pharmaceutical product” means a dosage form of an activeagent plus published material and optionally packaging.

“Providing” means giving, administering, selling, distributing,transferring (for profit or not), manufacturing, compounding, ordispensing.

“Published material” means a medium providing information, includingprinted, audio, visual, or electronic medium, for example a flyer, anadvertisement, a product insert, printed labeling, an internet web site,an internet web page, an internet pop-up window, a radio or televisionbroadcast, a compact disk, a DVD, an audio recording, or other recordingor electronic medium.

Food typically means a solid food or mixed solid/liquid food withsufficient bulk and fat content that it is not rapidly dissolved andabsorbed in the stomach. In one embodiment, food means a meal, such asbreakfast, lunch or dinner. The terms “taken with food”, “fed” and“non-fasted” are equivalent and are as given by FDA guidelines andcriteria. In one embodiment, with food means that the dosage form isadministered to a patient between about 30 minutes prior to about 2hours after eating a meal. In another embodiment, with food means thatthe dosage form is administered at substantially the same time as theeating the meal.

The terms “without food”, “fasted” and “an empty stomach” are equivalentand are as given by FDA guidelines and criteria. In one embodiment,fasted is means the condition wherein no food is consumed within 1 hourprior to administration of the dosage form or 2 hours afteradministration of the dosage form. In another embodiment, fasted meansthe condition wherein no food is consumed within 1 hour prior toadministration of the dosage form to 2 hours after administration of thedosage form.

Carisoprodol is a sparingly water soluble and lipophilic drug, and assuch, it may be expected that administration of carisoprodol in thepresence of a high fat meal will increase its bioavailability. Food canaffect gastric emptying, and may also alter the release of a drug from adosage form, the solubilization of the drug, and the transport of thedrug across the intestinal wall. For lipophilic, sparingly water solubledrugs, fatty meals can increase gastric residence time therebyincreasing the time available for solubilization and also may enhancethe solubilization of the drug by the lipids contained in the meal.Studies were thus undertaken to determine if administration ofcarisoprodol in the presence and absence of food has an effect on itspharmacokinetic parameters or those of its metabolite, meprobamate.

Unexpectedly, administration of carisoprodol in the presence of fooddecreases the C_(max) for carisoprodol compared to administration in theabsence of food. In one embodiment, administration of carisoprodol inthe presence of food (non-fasted) results in a 16% decrease in thegeometric mean of C_(max) for carisoprodol compared to administration inthe absence of food (fasted). Also unexpectedly, while the C_(max) forcarisoprodol decreases in the presence of food, the AUC_(0-t) andAUC_(0-INF) for carisoprodol remain substantially unchanged. In oneembodiment, according to current FDA criteria, by substantiallyunchanged, it is meant that there is a 90% Confidence Interval of 0.80to 1.25 for the ratio of the In transformed geometric mean of apharmacokinetic parameter (e.g., AUC) for the non-fasted state comparedto the fasted state. In one embodiment, the geometric mean of AUC_(0-t)and AUC_(0-INF) for carisoprodol remain substantially unchanged in thepresence and absence of food. In other words, the 90% confidenceinterval for the ratio of the geometric means between the non-fasted andfasted states is within the interval of 80-125% for ln-transformedAUC_(0-t) and AUC_(0-INF).

In addition to the pharmacokinetic parameters for carisoprodol, thepharmacokinetic parameters for meprobamate as a metabolite ofcarisoprodol were determined. In contrast to carisoprodol, the C_(max)and AUC (e.g., AUC_(0-t) and AUC_(0-INF)) for meprobamate as ametabolite of carisoprodol are both substantially unchanged in thepresence and absence of food. That is, there is a 90% ConfidenceInterval of 0.80 to 1.25 for the ratio of the in transformed geometricmean of AUC (e.g., AUC_(0-t) and AUC_(0-INF)) and C_(max) formeprobamate as a metabolite of carisoprodol in the non-fasted statecompared to the fasted state. In other words, the 90% confidenceinterval for the ratio of the geometric means between the non-fasted andfasted states is within the interval of 80-125% for ln-transformedC_(max), AUC_(0-t) and AUC_(0-INF).

A method of using carisoprodol comprises informing a user thatadministration of carisoprodol in the presence of food results in adecrease in the C_(max) for carisoprodol compared to administration inthe absence of food. A method of using carisoprodol comprises informinga user that administration of carisoprodol in the presence and absenceof food has no significant effect on the AUC (e.g., AUC_(0-t) andAUC_(0-INF)) for carisoprodol. In another embodiment, a method of usingcarisoprodol comprises informing a user that administration ofcarisoprodol is substantially bioequivalent in the presence and absenceof food. In one embodiment, the method further comprises informing auser that administration of carisoprodol in the presence or absence offood has no significant effect on the C_(max) and AUC (e.g., AUC_(0-t)and AUC_(0-INF)) for meprobamate as a metabolite of carisoprodol. Themethod may also include providing a patient in need of carisoprodol witha pharmaceutical formulation comprising a therapeutically effectiveamount of carisoprodol.

In another embodiment, a method of using carisoprodol comprisesinforming a user that administration of carisoprodol in the presence offood decreases the C_(max) of carisoprodol compared to administration inthe absence of food, and that the AUC of carisoprodol is substantiallyunchanged in the presence and absence of food.

In another embodiment, a method of using carisoprodol comprisesproviding a user with a pharmaceutical formulation comprising atherapeutically effective amount of carisoprodol, and informing thepatent that administration of carisoprodol in the presence of foodresults in a decrease in the C_(max) for carisoprodol compared toadministration in the absence of food.

In yet another embodiment, a method of using carisoprodol comprisesobtaining carisoprodol from a container providing information thatadministration of carisoprodol in the presence of food decreases theC_(max) of carisoprodol compared to administration in the absence offood.

An article of manufacture comprises a container holding a dosage formsuitable for administration of carisoprodol, and printed labelinginstructions providing a discussion that administration of carisoprodolin the presence of food decreases the C_(max) for carisoprodol comparedto administration in the absence of food. In addition, or alternatively,the printed labeling instructions inform that the carisoprodol should beadministered under fasted conditions, on an empty stomach, without food,greater than about 1 hour prior to a meal, at least about 2 hours afterconsumption of a meal, or a combination comprising one or more of theforegoing statements.

A method of manufacturing a carisoprodol pharmaceutical compositioncomprises packaging a carisoprodol pharmaceutical formulation along withinformation that administration of carisoprodol in the presence of fooddecreases the C_(max) for carisoprodol compared to administration in theabsence of food. In addition, or alternatively, the information advisesthat the carisoprodol should be administered under fasted conditions, onan empty stomach, without food, greater than about 1 hour prior to ameal, at least about 2 hours after consumption of a meal, or acombination comprising one or more of the foregoing statements.

The dosage form will typically be contained in a suitable containercapable of holding and dispensing the dosage form and which will notsignificantly interact with the composition and will further be inphysical relation with the appropriate labeling advising that thecarisoprodol formulation may be taken with or without food. The labelingmay be associated with the container by a means that maintains aphysical proximity of the two, by way of non-limiting example, they mayboth be contained in a packaging material such as a box or plasticshrink wrap or may be associated with the instructions being bonded tothe container such as with glue that does not obscure the labelinginstructions or other bonding or holding means.

In the foregoing embodiments, informing is by reference to publishedmaterial; by reference to a package active agent insert, a flyer or anadvertisement; by presentation of information at a seminar, conference,or other educational presentation; or by a conversation between apharmaceutical sales representative and the medical care worker.

In the foregoing embodiments, informing/information includes providing adiscussion that administration of carisoprodol in the presence of foodresults in a decrease in the C_(max) for carisoprodol compared toadministration in the absence of food. The informing/information mayinclude a statement that administration of carisoprodol in the presenceof food results in a 16% decrease in the geometric mean of C_(max) forcarisoprodol compared to administration in the absence of food. Inaddition to, or alternatively, the informing/information may include astatement that in a study of 22 patients, the geometric mean of C_(max)for carisoprodol when administered under non-fasted conditions was 1680ng/ml, and the geometric mean of C_(max) for carisoprodol whenadministered under fasted conditions was 2003 ng/ml.

The informing/information may further provide a discussion that the AUC(e.g., AUC_(0-t) or AUC_(0-INF)) for carisoprodol is substantiallyunchanged in the presence and absence of food. The informing/informationmay include a statement that administration of carisoprodol in thepresence of food results in substantially no difference in AUC_(0-t) orAUC_(0-INF) for carisoprodol. In one embodiment, informing provides adiscussion that the 90% confidence interval for the ratio of thegeometric means between the non-fasted and fasted states forcarisoprodol is within the interval of 80-125% for ln-transformedAUC_(0-t) and AUC_(0-INF). In one embodiment, the informing/informationmay provide a discussion that in a study of 22 patients, the geometricmean of AUC_(0-t) for carisoprodol was 6136 hr*ng/ml when administeredunder non-fasted conditions and 6385 hr*ng/ml when administered underfasted conditions. In one embodiment, the informing/information mayprovide a discussion that in a study of 22 patients, the geometric meanof AUC_(0-INF) for carisoprodol was 6306 hr*ng/ml when administeredunder non-fasted conditions and 6512 hr*ng/ml when administered underfasted conditions.

The informing/information may further include a statement thatadministration of carisoprodol in the presence of food has nosignificant effect on the C_(max) or AUC (e.g., AUC_(0-t) orAUC_(0-INF)) for meprobamate as a metabolite of carisoprodol. Theinforming/information may advise that the 90% confidence interval forthe ratio of the geometric means between the non-fasted and fastedstates for meprobamate as a metabolite of carisoprodol is within theinterval of 80-125% for ln-transformed AUC or C_(max). In addition to,or alternatively, the informing/information may include a statement thatin a study of 22 patients, the geometric mean of C_(max) for meprobamateas a metabolite of carisoprodol administered under non-fasted conditionswas 2352 ng/ml, and the geometric mean of C_(max) for meprobamate as ametabolite of carisoprodol administered under fasted conditions was 2280ng/ml. In one embodiment, the informing/information may provide adiscussion that in a study of 22 patients, the geometric mean ofAUC_(0-t) for meprobamate was 30745 hr*ng/ml as a metabolite ofcarisoprodol administered under non-fasted conditions and 30412 hr*ng/mlas a metabolite of carisoprodol administered under fasted conditions. Inone embodiment, the informing/information may provide a discussion thatin a study of 22 patients, the geometric mean of AUC_(0-INF) formeprobamate was 37942 hr*ng/ml as a metabolite of carisoprodoladministered under non-fasted conditions and 38005 hr*ng/ml as ametabolite of carisoprodol administered under fasted conditions.

In another aspect, a method of using carisoprodol comprises informing auser that carisoprodol affects the activity of cytochrome p450 isozymeCYP2C19; and that administration of carisoprodol with a substance withor without food can affect the plasma concentration, bioavailability,safety, efficacy, or a combination comprising at least one of theforegoing of carisoprodol or the substance.

In one embodiment, co-administration of carisoprodol with a second drugthat is metabolized by a cytochrome p450 isoform that metabolizescarisoprodol, e.g., cytochrome CYP2C19, can affect the metabolism of thecarisoprodol, the second drug, or both when taken with or without food.In one embodiment, the second drug comprises a narrow therapeutic indexdrug such as, for example, phenyloin or warfarin. Enzymes involved indrug metabolism such as cytochrome p450s respond to the constantlychanging amounts of substrate drugs they encounter. Administration of asubstrate drug in the presence of food can alter the amount of substratedrug available to the enzymes. Changes in drug metabolism due tocompetition variability caused by food with the same cytochrome p450isoform may change a clinical characteristic, e.g., the blood levels, ofa drug. In the case of a narrow therapeutic index drug, too little drugcan lead to insufficient therapeutic activity, while too large of a dosecan lead to excessive activity, both of which can be detrimental. Inparticular, co-administration of carisoprodol and a narrow therapeuticindex drug with or without food can lead to variable blood levels of thecarisoprodol, the narrow therapeutic index drug, or both.

A method of treatment comprises administering to a patient in need ofboth carisoprodol and a second drug, a therapeutically effective amountof both carisoprodol and the second drug, wherein the second drug is anarrow therapeutic index drug which is metabolized by cytochrome p450isoform CYP2C19, regularly monitoring the blood levels of the narrowtherapeutic index drug as AUC_(0-INF), C_(MAX), or a combinationcomprising one or more of the foregoing pharmacokinetic parameters, andinforming the patient that the amount bioavailability of the second drugmay be affected by the presence of food.

A method of using carisoprodol comprises informing a user that duringadministration of carisoprodol with a substance with or without food,the T_(max) for carisoprodol and the substance should be considered whendetermining the timing of administration of the carisoprodol and thesubstance. The substance comprises, for example, a narrow therapeuticindex drug. The method may also comprise informing that administrationof the carisoprodol and the narrow therapeutic index drug should betimed so that the C_(max) for carisoprodol and the C_(max) for thenarrow therapeutic index drug do not occur at similar times, or occur atthe most dissimilar times that can be achieved.

A method of treatment comprises administering to a patient in need ofboth carisoprodol and a second drug, a therapeutically effective amountof both carisoprodol and the second drug, wherein the second drug is anarrow therapeutic index drug which is metabolized by cytochrome p450isoform CYP2C19, and informing the patient that carisoprodol, the seconddrug, or both, should be taken consistently with food or consistentlywithout food. Administration consistently with or without food canreduce changes in a blood level of the carisoprodol, the substance, orboth.

A method of treatment comprises administering to a patient in need ofboth carisoprodol and a second drug, a therapeutically effective amountof both carisoprodol and the second drug, wherein the second drug is anarrow therapeutic index drug which is metabolized by cytochrome p450isoform CYP2C19, and informing the patient that carisoprodol, the seconddrug, or both, should be taken on an empty stomach, under fastedconditions, without food, greater than about 1 hour prior to a meal, atleast about 2 hours after consumption of a meal, or a combinationcomprising one or more of the foregoing statements.

A method of treatment comprises administering to a patient in need ofboth carisoprodol and a second drug, a therapeutically effective amountof both carisoprodol and the second drug, wherein the second drug is anarrow therapeutic index drug which is metabolized by cytochrome p450isoform CYP2C19, and informing the patient that carisoprodol, the seconddrug, or both, should be taken on a full stomach, under fed conditions,with food, within 30 minutes prior to a meal, within 2 hours after ameal, or a combination comprising one or more of the foregoingstatements.

Solid dosage forms for oral administration include, but are not limitedto, capsules, tablets, pills, powders, and granules. In such soliddosage forms, the active agent may be admixed with one or more of thefollowing: (a) one or more inert excipients (or carriers), such assodium citrate or dicalcium phosphate; (b) fillers or extenders, such asstarches, lactose, sucrose, glucose, mannitol, and silicic acid; (c)binders, such as carboxymethylcellulose, alignates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (d) humectants, such asglycerol; (e) disintegrating agents, such as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain complexsilicates, and sodium carbonate; (f) solution retarders, such asparaffin; (g) absorption accelerators, such as quaternary ammoniumcompounds; (h) wetting agents, such as cetyl alcohol and glycerolmonostearate; (i) adsorbents, such as kaolin and bentonite; and (j)lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and combinations comprisingone or more of the foregoing additives. For capsules, tablets, andpills, the dosage forms optionally comprise buffering agents.

The dosage forms described herein are optionally coated with afunctional or non-functional coating. The coating comprises about 0 wt %to about 40 wt % of the composition. Suitable coating materials includea polymer, such as a film-forming polymer including, for example, methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate,cellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, carboxymethyl cellulose,cellulose triacetate, cellulose sulphate sodium salt, poly(methylmethacrylate), poly (ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(phenylmethacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene),poly(ethylene) low density, poly (ethylene)high density, (polypropylene), poly(ethylene glycol poly(ethylene oxide), poly (ethyleneterephthalate), poly(vinyl alcohol), poly(vinyl isobutyl ether),poly(vinyl acetate), poly (vinyl chloride), polyvinyl pyrrolidone, andcombinations comprising one or more of the foregoing polymers.

In some applications, the polymer is a water-insoluble polymer. Waterinsoluble polymers include ethyl cellulose or dispersions of ethylcellulose, acrylic and/or methacrylic ester polymers, celluloseacetates, butyrates or propionates or copolymers of acrylates ormethacrylates having, for example, a low quaternary ammonium content,and the like, and combinations comprising one or more of the foregoingpolymers.

In some controlled-release applications, for example, the coating is ahydrophobic polymer that modifies the release properties of the API fromthe formulation. Suitable hydrophobic or water insoluble polymers forcontrolled-release include, for example, methacrylic acid esters, ethylcellulose, cellulose acetate, polyvinyl alcohol-maleic anhydridecopolymers, β-pinene polymers, glyceryl esters of wood resins, andcombinations comprising one or more of the foregoing polymers.

The inclusion of an effective amount of a plasticizer in the coatingcomposition may improve the physical properties of the film. Forexample, because ethyl cellulose has a relatively high glass transitiontemperature and does not form flexible films under normal coatingconditions, it may be advantageous to add plasticizer to the ethylcellulose before using the same as a coating material. Generally, theamount of plasticizer included in a coating solution is based on theconcentration of the polymer, e.g., most often from about 1 wt % toabout 50 wt % of the polymer. Concentrations of the plasticizer,however, can be determined by routine experimentation.

Examples of plasticizers for ethyl cellulose and other cellulosesinclude plasticizers such as dibutyl sebacate, diethyl phthalate,triethyl citrate, tributyl citrate, triacetin, and combinationscomprising one or more of the foregoing plasticizers, although it ispossible that other water-insoluble plasticizers (such as acetylatedmonoglycerides, phthalate esters, castor oil, etc.) can be used.

Examples of plasticizers for acrylic polymers include citric acid esterssuch as triethyl citrate NF, tributyl citrate, dibutyl phthalate,1,2-propylene glycol, polyethylene glycols, propylene glycol, diethylphthalate, castor oil, triacetin, and combinations comprising one ormore of the foregoing plasticizers, although it is possible that otherplasticizers (such as acetylated monoglycerides, phthalate esters,castor oil, etc.) can be used.

In certain embodiments, it is preferred that the coating is asubstantially continuous coat and substantially hole-free. Bysubstantially continuous coating is meant a coating which retains asmooth and continuous appearance when magnified 1000 times under ascanning electron microscope and wherein no holes or breakage of thecoating are evident.

Suitable methods can be used to apply the coating to the dosage form.Processes such as simple or complex coacervation, interfacialpolymerization, liquid drying, thermal and ionic gelation, spray drying,spray chilling, fluidized bed coating, pan coating, or electrostaticdeposition, may be used. A substantially continuous nature of thecoating may be achieved, for example, by spray drying from a suspensionor dispersion of the coating composition.

The coating, if present, are about 0.005 micrometers to about 25micrometers thick, preferably about 0.05 micrometers to about 5micrometers.

In one embodiment, a carisoprodol dosage form is an oral dosage formsuch as, for example, a tablet. Oral dosage forms comprise about 100 mgto about 1000 mg of carisoprodol, specifically about 200 to about 400 mgof carisoprodol, and more specifically about 350 mg of carisoprodol. Inone embodiment, the oral dosage form is an immediate-release oral dosageform.

EXAMPLES Example 1 Study of Carisoprodol Pharmacokinetics UnderNon-Fasted and Fasted Conditions

A biostudy was conducted under fasted and non-fasted conditions.

As used herein, for the purposes of biostudy and the determination ofbioequivalence, a fasted patient is defined as a patient who does noteat any food, i.e., fasts for at least 10 hours before theadministration of a dosage form of carisoprodol and who does not eat anyfood and continues to fast for at least 4 hours after the administrationof the dosage form. The dosage form is administered with 240 ml of waterduring the fasting period, and water can be allowed ad libitum after 2hours.

As used herein, for the purposes of biostudy and the determination ofbioequivalence, a non-fasted patient is defined as a patient who fastsfor at least 10 hours overnight and then consumes an entire test mealwithin 30 minutes of first ingestion. The dosage form is administeredwith 240 mL of water at 30 minutes after first ingestion of the meal. Nofood is then allowed for at least 4 hours post-dose. Water can beallowed ad libitum after 2 hours. A high fat test meal providesapproximately 1000 calories to the patient of which approximately 50% ofthe caloric content is derived from fat content of the meal. Arepresentative high fat high calorie test meal comprises 2 eggs fried inbutter, 2 strips of bacon, 2 slices of toast with butter, 4 ounces ofhash brown potatoes, and 8 ounces of whole milk to provide 150 proteincalories, 250 carbohydrate calories, and 500 to 600 fat calories.

The study was designed as a randomized, single-dose two-way crossover tocompare the pharmacokinetic parameters of SOMA®. Twenty-four healthyadults participated in this comparison study and 22 of the subjectscompleted the study. Subjects received two separate drug administrationtreatments in assigned periods, one treatment per period, according tothe randomization schedule. Dosing days were separated by a washoutperiod of at least seven days. Blood samples were drawn prior to dosing(pre-dose) and at 0.33, 0.67, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10,12, 18, and 24 hours post-dose. The samples were then analyzed forcarisoprodol and meprobamate.

The following pharmacokinetic parameters may be determined from theplasma concentration data:

The area under the plasma concentration versus time curve [AUC_(t)] maybe calculated using the linear trapezoidal rule from the zero time pointto the last measured concentration.

The area under the plasma concentration versus time curve from zero toinfinity [AUC_(0-INF)] may be calculated by adding C_(t)/K_(elm) to AUCwhere C_(t) is the last measured concentration and K_(elm) is theelimination rate constant.

The maximum observed plasma concentration [C_(max)] may be obtained byinspection. The C_(max) may also be designated as CMAX.

The time to maximum plasma concentration [T_(max)] may be obtained byinspection. If the same maximum plasma concentration occurs at more thanone time point, the first may be chosen as T_(max).

The terminal elimination rate constant [K_(elm)] may be obtained fromthe slope of the line, fitted by linear least squares regression,through the terminal points of the ln(base e) of the concentrationversus time plot for these points.

The half-life [T_(1/2)] may be calculated by the equationT_(1/2)=0.693/K_(elm).

The data for carisoprodol is shown in Tables 1 and 2:

TABLE 1 Ln-transformed pharmacokinetic parameters for carisoprodol 90%Confidence Non-Fasted, Fasted, Interval Geometric Geometric (Lowerlimit, upper Mean Mean % Ratio limit) C_(max) 1680 2003 83.8 (73.72,95.36) (ng/ml) AUC_(0-t) 6136 6385 96.1  (90.99, 101.51) (hr*ng/ml)AUC_(0-INF) 6306 6512 96.8  (91.8, 102.14) (hr*ng/ml)

TABLE 2 Non-transformed pharmacokinetic parameters for carisoprodolNon-Fasted, Fasted, Least Sq. Least Sq. Mean Mean % Ratio T_(max) (hr)2.24 1.63 137.5 k_(elm) 0.3713 0.376 98.7 T_(1/2) (hr) 1.95 1.95 100

The data for meprobamate, as a metabolite of carisoprodol, is shown inTables 3 and 4:

TABLE 3 Ln-transformed pharmacokinetic parameters for meprobamate asametabolite of carisoprodol 90% Confidence Non-Fasted, Fasted, IntervalGeometric Geometric (Lower limit, upper Mean Mean % Ratio limit) C_(max)2352 2280 103.1 (100.8, 105.5)  (ng/ml) AUC_(0-t) 30745 30412 101.1(99.4, 102.8) (hr*ng/ml) AUC_(0-INF) 37942 38005 99.8 (97.7, 102.0)(hr*ng/ml)

TABLE 4 Non-transformed pharmacokinetic parameters for meprobamat as ametabolite of carisoprodol Non-Fasted, Fasted, Least Sq. Least Sq. MeanMean % Ratio T_(max) (hr) 4.57 3.82 119.6 k_(elm) 0.0796 0.0753 105.6T_(1/2) (hr) 8.93 9.44 94.6

The conclusion from these data is that administration under non-fasted(i.e., fed) conditions decreases the C_(max) of carisoprodol compared toadministration under fasted conditions, however, the AUC of carisoprodolis substantially unchanged when administered in non-fasted compared tofasted conditions. In addition, the pharmacokinetic profile ofmeprobamate as a metabolite of carisoprodol is substantially unchangedwhen carisoprodol was administered under non-fasted compared to fastedconditions.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item.

The term “or” means “and/or”.

The terms “comprising”, “having”, “including”, and “containing” are tobe construed as open-ended terms (i.e., meaning “including, but notlimited to”).

The endpoints of all ranges directed to the same component or propertyare inclusive and independently combinable.

Unless defined otherwise, technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

Embodiments of this invention are described herein, including the bestmode known to the inventors for carrying out the invention. Variationsof those preferred embodiments may become apparent to those of ordinaryskill in the art upon reading the foregoing description. The inventorsexpect skilled artisans to employ such variations as appropriate, andthe inventors intend for the invention to be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications and equivalents of the subject matter recited in theclaims appended hereto as permitted by applicable law. Moreover, anycombination of the above-described elements in all possible variationsthereof is encompassed by the invention unless otherwise indicatedherein or otherwise clearly contradicted by context.

1. A method of administering carisoprodol, comprising: administeringcarisoprodol to a human patient in the presence of food. 2.-4.(canceled)
 5. The method of claim 1, wherein the administration ofcarisoprodol in the presence of food results in a 16% decrease in ageometric mean of C_(max) compared to administration in the absence offood.
 6. The method of claim 5, wherein in a study of 22 patients, thegeometric mean of C_(max) for carisoprodol when administered undernon-fasted conditions was 1680 ng/ml, and the geometric mean of C_(max)for carisoprodol when administered under fasted conditions was 2003ng/ml.
 7. The method of claim 5, wherein the AUC of carisoprodol issubstantially unchanged after administration of carisoprodol in thepresence or absence of food. 8.-9. (canceled)
 10. The method of claim 7,wherein the 90% confidence interval for the ratio of the geometric meansbetween the non-fasted and fasted states for carisoprodol is within theinterval of 80-125% for ln-transformed AUC_(0-t) or AUC_(0-INF).
 11. Themethod of claim 7, wherein in a study of 22 patients, the geometric meanof AUC_(0-t) for carisoprodol was 6136 hr*ng/ml when administered undernon-fasted conditions and 6385 hr*ng/ml when administered under fastedconditions.
 12. The method of claim 7, wherein in a study of 22patients, the geometric mean of AUC_(0-INF) for carisoprodol was 6306hr*ng/ml when administered under non-fasted conditions and 6512 hr*ng/mlwhen administered under fasted conditions.
 13. The method of claim 1,wherein administration of carisoprodol in the presence or absence offood has no significant effect on the C_(max) or AUC of meprobamate as ametabolite of carisoprodol. 14.-15. (canceled)
 16. The method of claim13, wherein the 90% confidence interval for the ratio of the geometricmeans between the non-fasted and fasted states for meprobamate as ametabolite of carisoprodol is within the interval of 80-125% forln-transformed AUC or C_(max).
 17. The method of claim 13, wherein in astudy of 22 patients, the geometric mean of C_(max) for meprobamate as ametabolite of carisoprodol administered under non-fasted conditions was2352 ng/ml, and the geometric mean of C_(max) for meprobamate as ametabolite of carisoprodol administered under fasted conditions was 2280ng/ml.
 18. The method of claim 13, wherein in a study of 22 patients,the geometric mean of AUC_(0-t) for meprobamate was 30745 hr*ng/ml as ametabolite of carisoprodol administered under non-fasted conditions and30412 hr*ng/ml as a metabolite of carisoprodol administered under fastedconditions.
 19. The method of claim 13, wherein in a study of 22patients, the geometric mean of AUC_(0-INF) for meprobamate was 37942hr*ng/ml as a metabolite of carisoprodol administered under non-fastedconditions and 38005 hr*ng/ml as a metabolite of carisoprodoladministered under fasted conditions.
 20. The method of claim 1, whereinthe patient is in need of a skeletal muscle relaxant.
 21. The method ofclaim 20, wherein the carisoprodol is in an oral dosage form.
 22. Themethod of claim 21, wherein the oral dosage form is a tablet.
 23. Themethod of claim 22, wherein the tablet comprises about 100 to about 1000mg of carisoprodol.
 24. The method of claim 23, wherein the tabletcomprises about 350 mg of carisoprodol. 25.-62. (canceled)
 63. A methodof manufacturing a carisoprodol pharmaceutical composition comprising:packaging a carisoprodol pharmaceutical formulation along withinformation that administration of carisoprodol in the presence of fooddecreases the C_(max) for carisoprodol compared to administration in theabsence of food. 64.-92. (canceled)
 93. A method of maximizing the peakplasma concentration of carisoprodol experienced by a patient,comprising: administering a carisoprodol dosage form to a human patientin need thereof under fasted conditions. 94.-110. (canceled)
 111. Themethod of claim 93, wherein the patient is in need of a skeletal musclerelaxant.